Naturally occurring human EPO is produced by the kidney and is the humoral plasma factor which stimulates red blood cell production. It stimulates the division and differentiation of committed erythroid progenitors in the bone marrow. (Goldwasseret et al., J. Biol. Chem., 249, 4202-4211, 1974, Sherwoodet et al., Endocrinology, 103, 866-870, 1978). It is produced in adult kidneys (Sherwood et al., Endocrinology, 103, 866-870, 1978) and in fetal liver (Zanjani et Al., J. Lab. Clin. Med., 89, 640-644, 1977).
The administration of a pharmaceutical composition of EPO to the organism stimulates and/or accelerates the production of erythrocytes. The pharmaceutical composition of EPO is used in the treatment of chronic renal failure, anemia secondary to chemotherapy treatment in cancer and anemia associated with zidovudine treatment of human immunodeficiency virus infection and in the treatment of other kinds of anemias (Danna et al., Erythropoietin in Clinical Applications—An International Perspective. New York, N.Y.: Marcel Dekker; 301-324, 1990; Eschbach in sod., N. England J. of Med., 316, 2, 73-78, 1987; Krane, Henry Ford Hosp. Med. J., 31,3,177-181, 1983).
Recombinant EPO, which is the product of expression of the human EPO gene in mammalian cells is used in pharmaceutical compositions of EPO (EP 148605, EP 205564, EP255231). Also some EPO analogs and derivatives are described in the art: EP640619, EP 668351, WO 9412650, EP1064951, WO 0232957, WO 9533057, U.S. Pat. No. 5,916,773, WO 09902710, U.S. Pat. No. 5,580,853, U.S. Pat. No. 5,747,446, U.S. Pat. No. 5,919,758 and U.S. Pat. No. 6,107,272.
Pharmaceutical compositions of EPO, which comprise human serum albumin, are described in: EP 178665, EP 178576, U.S. Pat. No. 5,661,125, WO 0061169. Human serum albumin can cause allergic reactions (Stafford C T et al., Ann Allergy, 61(2), 85-88, 1988). Furthermore there exist a risk of infection with viruses when a pharmaceutical composition comprises human blood products. Therefore pharmaceutical formulations of EPO that are stable and are free of human blood products, such as albumin are needed.
EP 306824, EP 607156, EP 528313 and EP 528314 describe pharmaceutical compositions, in which urea is used as an EPO stabilising agent.
EP306824, EP 178665, GB 2171304, EP 528314, EP 528313 and EP 1002547 describe lyophilized formulations of EPO.
U.S. Pat. No. 5,376,632 describes a pharmaceutical formulations, in which alpha and beta cyclodextrines are used.
EP 607156, EP 528313 in EP178665 describe aqueous pharmaceutical compositions of EPO, which comprise antimicrobial preservatives such as benzyl alcohol, parabens, phenols, and mixtures thereof.
EP 909564, EP 528314, EP 430200 and WO 0061169 describe the use of aminoacids and/or the combination of aminoacids and non-ionic detergents as stabilising agents.
WO 0187329 describes different pharmaceutical compositions of pegylated EPO analog. The described pharmaceutical compositions are essentially based on the use of sulfate buffer.
Some of the pharmaceutical compositions of EPO described in: RU 2128517, WO0061169, EP 528313, EP 607156, EP 528314, EP 178665, are prepared in citrate buffer.